This is a clinical project, with the primary purpose of managing and treating the NIH kidney recipients and collecting long-term clinical data. The overall evaluation of the NIH kidney transplant program will be performed toward the end of 2011, when most participants will have completed the protocols. The following is an example of analysis of the transplant database, presented at the Annual American Society of Nephrology meeting in 11/2000. A randomized clinical trial comparing tacrolimus and sirolimus maintenance monotherapy following kidney transplantation ME Cho1, X Zhao2, MS Ring1, RB Mannon3, AD Kirk4 1 Kidney Disease Branch, NIDDK;2Office of the Director, NIDDK, NIH, Bethesda, MD;3University of Alabama, Birmingham, AL;4Emory University, Atlanta, GA Background: Both sirolimus (Rapa) and tacrolimus (FK) are effective in preventing renal allograft rejection when used as part of a multidrug regimen, but there have been no studies directly comparing these agents as monotherapies. Methods: In order to investigate whether there was a clear advantage to either drug, we enrolled 31 patients in a phase II trial using Thymoglobulin and methylprednisolone induction followed by combination therapy with both Rapa and FK for 6 months. At 6 months, those without rejection on protocol biopsy with good tolerance to both drugs were randomized either Rapa or FK monotherapy. Primary outcome was renal graft function over time, using linear mixed model to calculate the least mean square values of serum creatinine for repeated measurements. The secondary outcomes included safety and tolerability profiles and renal graft biopsy results. Results: Out of 31 patients, 7 were randomized to Rapa and 8 to FK. The remaining 16 patients could not be randomized due to Rapa intolerance oral ulcers (1);hyperlipidemia (2);arthropathy (3), rejection on protocol biopsy (4), or unrelated issues (6). The mean follow-up was 4 yrs post randomization. Their mean nadir serum Cr (mg/dL) was 1.03 in Rapa group and 1.17 in FK group and remained stable over 54 months without significant increase. There were no differences in the rates of biopsy diagnoses of IF/TA, rejection, or BK nephropathy in the two groups, based on a mean of 3.5 biopsies per patient over a mean of 1.4-year period. Serum triglycerides levels were significantly higher in the Rapa group between months 6-24, and the absolute lymphocyte count remained significantly lower in Rapa group between months 12-30. The incidence of post transplant diabetes was similar in both groups. Conclusion: In patients selected for their stability and tolerance to either drug, both Rapa and FK monotherapy provided similar prophylaxis from rejection without differing long-term consequences over a 4 year follow-up period. FK was associated with fewer dose limiting consequences. The following is an abstract submitted to the Annual American Society of Nephrology for 2011: Mycophenolate Mofetil Induced Duodenal Villous Atrophy in a Renal-Transplant recipient and its Effect on Tacrolimus and Lipid Levels CHO ME1, Glenn S1, Chamberlain CE2, Kleiner D3, Hon YY2 1 Kidney Disease Branch, NIDDK;2Clinical Center Pharmacy, Clinical Center;3Department of Laboratories, NCI, NIH, Bethesda, MD Mycophenolate mofetil (MMF) commonly causes diarrhea, typically early following drug initiation. We report an atypical case of MMF-associated diarrhea in a 28 year-old kidney transplant recipient, starting after 41 months of maintenance therapy with tacrolimus (FK) and MMF. Infectious etiologies were excluded and the anti-motility agents failed to improve his symptoms. He developed sharp increase in FK levels from 5 to 19 ng/mL, despite having his dose reduced. His LDL decreased from 79 to 16 mg/dL in the setting of stable statin therapy and 4-fold increase in transaminases. figure1 Esophago-gastroduodenoscopic biopsies revealed marked shortening of duodenal villi with repair and regenerative changes, consistent with drug effect and MMF was stopped. Within a few days, his diarrhea improved and completely resolved within 4 weeks. His FK level, lipid profile and transaminases returned to baseline values within 8 weeks. Genotyping revealed that the patient is a homozygous variant for CYP3A5 6986A>G and ABCB1 1236C>T, 2677G>T/A, and 3435C>T, indicating that CYP3A4 is the enzyme primarily involved in drug bioavailability and metabolism. While few case reports have described duodenal villous atrophy with MMF use recently, it is important to consider the effect of intestinal barrier disruption on drug absorption and consequent renal and hepatic toxicities. Possible underlying mechanisms include reduced CYP3A4 expression/activity due to duodenal villi shortening, complex interplay between p-glycoprotein and CYP3A genotype and phenotype, and potential FK-statin interaction.